This Mid-Career Investigator Award (K24) will provide the candidate with an opportunity to continue his career development, to continue to mentor beginning clinical investigators and to continue research in the pharmacotherapy of alcoholism and the genetics of alcohol and drug dependence. The research plan includes five projects, three of which have been funded and are ongoing; the others are being considered for funding or under scientific review. The ultimate research goal of proposal is the synthesis of findings from neuropsychopharmacology and genetics to yield a coherent pharmacogenetic approach to the etiology and treatment of alcoholism. The specific research aims of the proposal are 1) to complete data analysis and report preparation for a study of targeted naltrexone for early problem drinkers (data collection for which was recently completed), 2) to complete ongoing studies of the genetics of cocaine dependence (CD) and opioid dependence (OD), 3) to conduct a study of the genetics of alcohol dependence (AD) using the method of linkage disequilibrium and 4) to conduct a study examining the safety, efficacy, mechanism of action and duration of effects of sertraline in alcoholics who are subtyped by age of alcoholism onset. The mentoring plan will focus on training psychiatric residents, postdoctoral fellows in addiction psychiatry, postdoctoral fellows in alcohol research, and junior faculty in psychiatry and medicine to conduct patient-oriented research. That training will focus on clinical research methods, data interpretation, manuscript and grant preparation, research ethics and human subjects protections. Mentoring will occur through trainees' participation in the research projects and through lectures and seminars that are offered through the Alcohol Research Center, Department of Psychiatry, and the General Clinical Research Center at the University of Connecticut School of Medicine. This range of research and educational activities offers a rich matrix of opportunities for trainees and junior investigators in patient-oriented research. In addition, the K24 will enable the candidate to take coursework in areas that are important to his continued development as an investigator and mentor. Over the next five years, the candidate seeks to: 1) maintain full-time effort in research and research mentoring, 2) increase the depth and breadth of his own skills through specific training in molecular genetics, biostatistics and bioinformaties and through continued collaboration with established experts in these areas, 3) continue the dissemination of research findings through presentation at scientific meetings and publication in the scientific literature and 4) help to train the next generation of investigators who will advance the field of patient-oriented research in alcoholism and drug dependence.